The present invention is directed, in part, to novel methods of treating complicated anosmia in a mammal, to methods of enhancing the rate of olfactory nerve recovery in a mammal, and to methods of enhancing nerve regeneration in a mammal.
Injuries to the central nervous system (CNS), such as, for example, stroke, chronic nasal sinus disease, allergic rhinitis, neurodegenerative disease, head trauma, viral or bacterial infection, and surgery, can result in olfactory dysfunction, which affects nearly three million Americans. A complete loss of smell is referred to as xe2x80x9canosmiaxe2x80x9d whereas a decrease in smell sensitivity is referred to as xe2x80x9chyposmia.xe2x80x9d Unfortunately, there is little that can be done to cure or treat the condition effectively. Further, recovery from head trauma can take many months or even years and is often incomplete even after apparent physical recovery.
The ability of the olfactory system to replace degenerating olfactory neurons caused by age or injury has been examined. Morphological studies have demonstrated degeneration of mature olfactory neurons in the olfactory epithelium after axotomy, followed by an increase in the proliferation of basal cells. Cancalon et al., J. Cell Biol., 1980, 84, 779-794; Graziadei et al., J. Cell Biol., 1973, 59, 525-30; Graziadei and Monti Graziadei, The olfactory system: a model for the study of neurogenesis and axon regeneration in mammals. In: C. W. Cotman (Ed.), Neuronal Plasticity, New York, Raven Press, 1978, pp. 131-153; Oley et al, J. Comp. Physiol. Psychol, 1975, 88, 477-495; and Simmons et al., J. Neurophysiol., 1981, 45, 529-549. With time, the basal cells differentiate into olfactory neurons that can connect to the olfactory bulb and restore function. Costanzo, Brain. Res., 1985, 361, 258-266 and Yee et al., Physiol. Behav., 1995, 58, 959-968. Few studies, however, have examined possible ways to improve recovery after denervation. The time for some recovery of behavioral function varies with species; in hamsters, for example, recovery occurs in approximately 20 days. Anatomical recovery is reported to take about 30 days in most species studied. Cummings et al., J. Comp. Neurol., 2000, 421, 362-373; Monti Graziadei et al., J. Neurocytol., 1979, 8, 197-213; Graziadei and Monti Grazaiadei, The olfactory system: a model for the study of neurogenesis and axon regeneration in mammals. In: C. W. Cotman (Ed.), Neuronal Plasticity, New York, Raven Press, 1978, pp.131-153. Within the central nervous system, it is thought that minimal regeneration occurs, except for a population of stem cells within the subventricular zone that proliferate and are thought to contribute to cell repopulation in the olfactory bulb. Gheusi et al., Proc. Natl. Acad. Sci. USA, 2000, 97, 1823-1828.
Vitamin A has been used to treat uncomplicated anosmia but was found not to be useful in treating anosmia associated with skull injuries and fractures with sheering of olfactory nerves, i.e., complicated anosmia. Duncan et al., Archives of Otolaryngology, 1962, 75, 116-124. Recent evidence has demonstrated that retinoic acid (RA), a metabolite of vitamin A, plays an important role in the development and morphogenesis of the fetal olfactory system. Anchan et al., J. Comp. Neurol., 1997, 379, 171-184; LaMantia et al., Neuron, 1993, 10, 1035-1048; and Simmons et al., J. Neurophysiol., 1981, 45, 529-549. There is also evidence that RA plays a role in the growth of the adult olfactory system. Gustafson et al., Dev. Brain Res., 1999, 114, 121-126; Whitesides et al., J. Comp. Neurol., 1998, 394, 445-461; Zhang, Biochem. Biophys. Res. Commun., 1999, 256, 346-351; and Corcoran et al., Nat. Neurosci., 1999, 2, 307-308. Vitamin A has been postulated to have an effect on mRNA expression levels of olfactory marker protein (Aderoju et al., Amer. Chem. Soc. Abstracts, 2000, Abstract 193) and gene expression in neurons in vivo (Asson-Barres et al., Amer. Chem. Soc. Abstracts, 2000, Abstract 195). In addition, retinoic acid has been postulated to play a role in olfactory epithelium via retinoic acid binding proteins (Ahmad et al., Amer. Chem. Soc. Abstracts, 2000, Abstract 194). Thus, methods of treating complicated anosmia in mammals, enhancing the rate of olfactory nerve recovery in mammals, and enhancing nerve regeneration in mammals is greatly needed.
The present invention is directed to, inter alia, methods of treating complicated anosmia in a mammal comprising administering an effective amount of a retinoid compound to the mammal.
The present invention is also directed to methods of enhancing the rate of olfactory nerve recovery in a mammal after injury comprising administering an effective amount of a retinoid compound to the mammal.
The present invention is also directed to methods of enhancing nerve regeneration in a mammal comprising administering an effective amount of a retinoid compound to the mammal.